Genetic analyses of humans with GnRH deficiency (Kallmann's Syndrome [KS] and normosmic idiopathic hypogonadotropic hypogonadism [nIHH]) have provided unique insights into the genes controlling sexual maturation (KAL1, GNRHR, FGFR1, and GPR54). The discovery that FGFR1 mutations causes KS demonstrated a critical role of FGF signaling in olfactory bulb morphogenesis and GnRH neuron migration. However, one important and unsolved issue in GnRH neuronal development is the identification of the physiologic FGF(s) for FGFR1 in GnRH ontogeny. Furthermore, FGF signaling controls a plethora of critical biologic processes throughout development, including cell fate, cell migration, and cell survival, but the mechanism by which such widespread FGF signaling is tightly regulated and specialized remains unknown. The coordinate spatial and temporal expression of several genes within the FGF signaling pathway -FGF8 syn- expression group- suggests an evolutionarily conserved genetic network, including inhibitors and enhancers of FGF8 signaling. We hypothesize that the FGF8 syn-expression group modulates FGF signaling during GnRH neuron development and has a key role in human reproduction. Therefore, the aims of this proposal are to: 1) Identify key components of the FGF pathway critical for GnRH ontology 2) Perform genotype-phenotype correlations for mutations in the FGF pathways causing IHH, and 3) Study mutant FGF protein using crystallography and molecular and cell biology techniques. PUBLIC HEALTH RELEVANCE: The information generated from the proposed studies will increase our understanding of the genetics of sexual maturation. It will also provide valuable genotype-phenotype information that will have clinical relevance for both children and adults in terms of diagnosis and understanding of the mechanism of pubertal disorders as well as initiating new opportunities for genetic counseling. Further, these genetic studies will provide critical pathophysiologic insights into the role of FGF8 signaling pathway in human reproduction. Such understanding is required to design future targeted therapies. In general terms, the focus of this project is to explore the genetic causes of reproductive conditions and will provide a foundation for understanding, diagnosing, and genetic counseling of these disorders.